Intellipharmaceutics International Inc. (IPCI)

[WeeZuhl]

citing 1 single isolated case of faulty manufactured blue dye colored feeding tubes from 33 years ago to attempt to build an asinine case against IPCI's use of FDA blue dye # 1 in Rexista is as hilarious as these forums get.

Pulmonary and Critical Care Medicine, 2016









https://oatext.com/pdf/PCCM-1-111.pdf

Absorption of FD&C Blue No. 1 from enteral feedings: A
look back at a patient safety effort with modern relevance
James P Maloney and Tracey A Brand
Pulm Crit Care Med, 2016 Volume 1(2): 52-57

Discussion
By 2000 the blue dye enteral feed tinting method was entrenched in most U.S. intensive care units as a bedside monitor of aspiration. As there had only been 11 published case reports of FD&C Blue No. 1 absorption by 2001 (including abstracts) its occurrence appeared to be uncommon. However, our 2002-3 survey reported herein of enteral feeding providers indicated that FD&C Blue No. 1 absorption from enteral feedings was in fact a widely recognized but underreported adverse event. For perspective, at the time in the United States there were an estimated 2,144 hospital-based dietitians and 10,244 intensivists (1996 data); yet we surveyed only 50 of each. None of the cases reported had previously been communicated to regulatory agencies. Thus dye absorption among critically-ill, enterally-fed patients was more common than previous reports suggested and was widely underreported. Almost all patients were in ICUs and had sepsis, an illness associated with increased gut permeability, suggesting that a permissive context was required for dye absorption.

That dietitians were more likely to have encountered dye absorption and to provide case details is not surprising, as dietitians care for proportionally more enterally-fed patients. While it is intuitive to suspect that administration of larger dye quantities for longer periods (creating a larger intestinal load) is a prerequisite for dye absorption [15], in our survey absorption of FD&C Blue No. 1 occurred in cases even after a few days and when a commercial dye-pellet tubing was used, designed to deliver 10 mg dye/hr (within FDA guidelines at the time for healthy subjects). In fact, the dye-pellet tubing was as commonly associated with dye absorption as the addition of dye from multidose bottles. Moreover, the 7 deaths among these 17 subjects occurred in those administered the dye-pellet system. Due to possible reporting and time bias (the drip pellet system was a more recently marketed device, and may have been used exclusively in some hospitals), we cannot ascribe a higher mortality to use of either system, and notably deaths have been reported with various dye addition methods.

That the 5 blue skin discoloration cases reported here and that 4 previously reported cases of blue skin discoloration associated with FD&C Blue No. 1 absorption all died shortly thereafter is concerning. The only report of survival after blue skin discoloration was in a child [11]. The high mortality associated with blue skin discoloration is consistent with a mechanism where high tissue concentrations of absorbed dye inhibit mitochondrial respiration. FD&C Blue No. 1 is a triphenylmethane dye derived from coal tar with potent inhibitory effects on mitochondrial respiration in-vitro, decreasing oxygen uptake in liver mitochondria by 78% at 0.1 mg/ml and by 90% at 0.8 mg/ml (1 mM). These are concentrations at which FD&C Blue No. 1 will discolor serum green and blue, respectively. The mechanism of this inhibition is consistent with inhibition of ADP translocation across the inner mitochondrial membrane by structural mimicry of the purine ring, a similar mechanism as the poison atractyloside [20]. In a child who died after absorbing FD&C Blue No. 1 from enteral feeds, blue skin and serum indicated a serum dye concentration near 1 mg/ml [2], and hyperthermia, refractory shock, and acidosis suggested in-vivo uncoupling of respiration. However, hyperthermia was not reported by our respondents. Interestingly, most reported deaths following FD&C Blue No. 1 absorption from enteral feedings, including in this survey, have occurred during sepsis. Mitochondrial dysfunction is a key feature of sepsis linked with poor outcomes [21], and further dysfunction due to absorbed dye may exacerbate these effects [22].

The potential for in-vivo toxicity of absorbed FD&C Blue No. 1 in humans is supported by animal studies where chronic subcutaneous injections of it were associated with dramatic increases in mortality. Such unexpected toxic effects from parenteral dye in studies designed to assess carcinogenic potential were apparently deemed irrelevant to the safety of a food dye deemed nonabsorbable in healthy animals. In 1982 the FDA recognized that existing studies were too small [26], and larger studies were commissioned in rodents that again suggested oral FD&C Blue No. 1 was safe [27]; yet further parenteral administration studies were not pursued. All animals were healthy in these studies, and thus would have normal gut permeability. Such work emphasizes that the safety of artificial food dyes, whether in enteral feedings or in foods, is predicated on their remaining nonabsorbable. The FDA never approved FD&C Blue No. 1 for use in enteral feeds except with a dye-pellet device, but FDA guidelines on acceptable ingestion in healthy adults of 12 mg/kg/day were extrapolated toward its use in enteral feeds [2,26].

Dye absorption in our survey occurred in diseases associated with increased gut permeability, mostly sepsis, but also with chronic illnesses like inflammatory bowel disease. Of note, ICU admission itself has been associated with enhanced gut permeability [16]. Our findings combined with prior animal and human evidence suggest that the long-term safety of artificial food dyes in individuals with chronic illnesses that increase gut permeability (celiac sprue, atopic disease) should also be regarded as unestablished. In healthy animals 90% of intravenously administered FD&C Blue No. 1 is excreted in bile, with only 10% excreted in urine [26,30]. Once absorbed from a leaky gut, FD&C this dye travels a classic enterohepatic cycle of biliary excretion and gut reabsorption where substantial liver exposure may occur before any discoloration is apparent [2]. Absorbed dye likely impairs function of the mitochondria-rich liver. Of relevance, marked blue-green liver discoloration was seen at autopsy in a patient who died after 14 days of FD&C Blue No. 1 in enteral feeds [15].

As our survey was not a randomized sampling of providers, we cannot extrapolate a national incidence of dye absorption cases then, nor can we rule out an ascertainment bias for clinicians more likely to have encountered dye absorption. Exclusion of gut perforation as a risk factor for dye absorption was not always possible due to a paucity of autopsies (gut perforation was identified in 3 cases at surgery, but was absent in the 2 autopsied cases), but it was not been reported in other published cases of dye absorption [2,7]. Other substances that can cause blue skin or green urine discoloration (amiodarone, propofol) cannot explain these cases given a minimal prevalence and/or the lack of absorption peaks for these drugs in assayed fluids in this and other reports [31-33].

Prospective studies had shown that the blue dye practice had a low sensitivity for aspiration detection, yet it was still embraced [3,34]. In 2002 consensus committee guidelines had recommended that the blue dye practice be abandoned based on poor sensitivity and potential for harm [35]. Yet the blue dye method continued to be utilized in American hospitals, with 48% of providers in a 2002 survey indicating their hospitals continued its use (though use had declined since 1999) [36]. At the same time, evidence-based measures shown to prevent aspiration remained underutilized [35,37]. Patient positioning with the torso elevated 30-45° in enterally-fed mechanically ventilated patients had been shown to decrease gastroesophageal reflux, aspiration, and nosocomial pneumonia in prospective studies published as far back as 1992 [1,37-39]. Nonrecumbent positioning was recommended for nosocomial pneumonia prevention by the Centers for Disease Control and the FDA [40], but it remained underutilized until promulgated over the ensuing decade by multiple safety-based organizations such as the Institute for Health Care Safety, the Leapfrog Group, and the National Advisory Forum. At our request, the 17 detailed cases identified in our survey were subsequently reported to the FDA by providers with our assistance, and were reviewed by the FDA preparatory to the drafting of their Public Health Advisory in September 2003 regarding potential hazards of this practice.

Conclusions
We found in 2002-3 that FD&C Blue No. 1 absorption was a well-recognized and underreported complication of enteral feeding in critically-ill patients who had common illnesses such as sepsis that increase gut permeability. Death in all patients with blue skin discoloration suggests that toxic properties of FD&C Blue No. 1 caused adverse effects in-vivo. The tinting of enteral feedings with FD&C Blue No. 1 was abandoned in the USA after a US FDA Health advisory in 2003 as it was an insensitive practice that was never evidence-based, and was potentially unsafe due to the ubiquitous illnesses that increase gut permeability and thus dye absorption. Our patient safety efforts with collecting, reporting, and analyzing data from this survey, as well as facilitating reports to the FDA, are a useful example for young clinicians interested in patient safety projects and provide a cautionary reminder of the potential downfalls of non-evidence based medical practices.